Hypoglycemia, the most common complication of insulin therapy in the diabetic, principally affects the brain. Despite this, little is known of the long term consequences of hypoglycemia or how the brain adapts to it. In preliminary studies using rats with hypoglycemia due to an implanted insulinoma we have found that (1) these rats develop specific neurological symptoms (2) their brains adapt by increasing the extraction of glucose and (3) their cerebral microvessels metabolize glucose at an accelerated rate. The overall objective of this proposal is to determine the basis for these adaptations, how they protect the brain, and when insufficient, the nature of the resultant damage. We will test the following hypotheses: (1) Glucose extraction by the brain of the insulinoma rat is increased by chronic hypoglycemia and not by insulin or other tumor products. (2) Chronic hypoglycemia enhances glucose extraction by increasing its transport across the blood-brain barrier. If so, it does this by increasing the number of glucose transporters in brain capillaries. (3) When the adaptation of glucose extraction is insufficient to maintain the fuel needs of the brain, it will either utilize other fuels or diminish its fuel requirements by lowering body temperature. (4) Seizures and other neurological symptoms will occur at lower glucose concentrations in adapted than in non-adapted rats. Conversely, seizures will occur in chronically hyperglycemic (diabetic) rats, at higher glucose concentrations. (5) Certain regions of the brain are vulnerable to chronic hypoglycemia even when overall brain adaptation occurs. These areas can be identified using the 2-deoxyglucose technique and or by analyzing neurobehavioral changes and brain histopathology. (6) Quantitatively similar, but less marked, alterations in brain metabolsim, function and pathology occur in rats with intermittent hypoglycemia. These studies should provide insights into the adverse effects of hypoglycemia in normal and diabetic subjects and the ameliorating adaptations that help to prevent them.